Biliverdin inhibits Toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase
Biliverdin inhibits Toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase
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DOI：
10.1073/pnas.1108571108
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发表时间：
2011-11-15
影响因子：
11.1
通讯作者：
Otterbein, Leo E.
中科院分区：
文献类型：
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作者：
Wegiel, Barbara;Gallo, David;Otterbein, Leo E.
对炎性应激物的细胞反应需要促炎细胞活化，随后是反应的受控解决以恢复稳态。我们假设胆绿素还原酶（BVR）通过与胆绿素（BV）结合，通过内皮型一氧化氮合酶（eNOS）的磷酸化来抑制细胞对内毒素诱导的炎症反应。所产生的NO又使BVR亚硝酰化，导致核转位，其中BVR在Ap-1位点与Toll样受体-4（TLR 4）启动子结合以阻断转录。我们发现在巨噬细胞中BV诱导的eNOS磷酸化（Ser-1177）和NO产生部分由Ca（2+）/钙调素依赖性激酶介导。此外，我们表明，BVR是S-亚硝基化的三个半胱氨酸之一，这种翻译后修饰是BVR介导的信号。BV诱导的BVR核转位和TLR 4表达抑制在来自Enos（-/-）小鼠的巨噬细胞中丧失。在小鼠体内，BV提供保护急性肝损伤，是依赖于NO的可用性。总的来说，我们阐明了BVR在调节炎症反应的内毒素，需要eNOS衍生的NO和TLR 4信号在巨噬细胞的机制。
The cellular response to an inflammatory stressor requires a proinflammatory cellular activation followed by a controlled resolution of the response to restore homeostasis. We hypothesized that biliverdin reductase (BVR) by binding biliverdin (BV) quells the cellular response to endotoxin-induced inflammation through phosphorylation of endothelial nitric oxide synthase (eNOS). The generated NO, in turn, nitrosylates BVR, leading to nuclear translocation where BVR binds to the Toll-like receptor-4 (TLR4) promoter at the Ap-1 sites to block transcription. We show in macrophages that BV-induced eNOS phosphorylation (Ser-1177) and NO production are mediated in part by Ca(2+)/calmodulin-dependent kinase kinase. Furthermore, we show that BVR is S-nitrosylated on one of three cysteines and that this posttranslational modification is required for BVR-mediated signaling. BV-induced nuclear translocation of BVR and inhibition of TLR4 expression is lost in macrophages derived from Enos(-/-) mice. In vivo in mice, BV provides protection from acute liver damage and is dependent on the availability of NO. Collectively, we elucidate a mechanism for BVR in regulating the inflammatory response to endotoxin that requires eNOS-derived NO and TLR4 signaling in macrophages.